What are the possible causes of thrombocytosis in a patient with a platelet count of 661 × 10⁹/L and a negative JAK2 mutation test?

Causes of Thrombocytosis with Platelet Count 661 × 10⁹/L and Negative JAK2

With a platelet count of 661 × 10⁹/L and negative JAK2 mutation, you must systematically evaluate for CALR or MPL mutations to identify essential thrombocythemia, then exclude reactive causes including infection, inflammation, iron deficiency, malignancy, and tissue injury. 1

Primary (Clonal) Thrombocytosis Causes

Essential Thrombocythemia (ET) with Alternative Driver Mutations

• CALR mutations are present in approximately 25-30% of ET patients who are JAK2-negative, making this the most likely primary cause in your patient 1, 2
• MPL mutations (W515L/K) account for 3-5% of ET cases and should be tested if CALR is negative 1, 3
• Approximately 10-15% of ET patients remain "triple-negative" (JAK2/CALR/MPL all negative) but still meet WHO diagnostic criteria through bone marrow morphology and exclusion of reactive causes 1, 2

Diagnostic Criteria for ET (WHO 2016)

The diagnosis requires all four major criteria 1:

1. Platelet count ≥450 × 10⁹/L (your patient meets this at 661)
2. Bone marrow biopsy showing megakaryocyte proliferation with large, mature morphology without significant left-shift of granulopoiesis or erythropoiesis
3. Not meeting criteria for other myeloid neoplasms (CML, PV, PMF, MDS)
4. Presence of JAK2, CALR, or MPL mutation OR presence of another clonal marker OR absence of evidence for reactive thrombocytosis

Other Myeloproliferative Neoplasms to Exclude

• Pre-fibrotic primary myelofibrosis (pre-PMF) can present with thrombocytosis and negative JAK2 but shows distinct bone marrow morphology with extensive megakaryocyte clustering and atypia 1
• MDS with ring sideroblasts and thrombocytosis (MDS-RS-T) presents with thrombocytosis ≥450 × 10⁹/L, ring sideroblasts ≥15%, and frequently harbors SF3B1 mutations alongside JAK2 or MPL mutations 1
• Polycythemia vera is excluded by normal hemoglobin/hematocrit 1

Secondary (Reactive) Thrombocytosis Causes

Most Common Reactive Causes

• Tissue injury accounts for 32.2% of secondary thrombocytosis cases and includes surgery, trauma, burns, and tissue necrosis 4
• Infection (acute or chronic bacterial, viral, fungal) is a frequent trigger 4, 3
• Chronic inflammatory disorders including inflammatory bowel disease, rheumatoid arthritis, vasculitis 4, 3
• Iron deficiency anemia is a critical cause to exclude with serum ferritin, iron studies 4, 3
• Malignancy (solid tumors, lymphoma) through cytokine production 4, 3
• Post-splenectomy or functional hyposplenism causes persistent thrombocytosis 4, 3

Key Distinguishing Features

• Reactive thrombocytosis typically shows platelet counts <1000 × 10⁹/L, though overlap exists 3, 5
• Absence of splenomegaly favors reactive causes (splenomegaly suggests clonal disorder) 5
• Normal bone marrow morphology without megakaryocyte clustering or atypia 1, 3
• Resolution with treatment of underlying condition confirms reactive etiology 4

Diagnostic Algorithm

Immediate Next Steps

1. Order CALR and MPL mutation testing immediately—these identify 85-90% of JAK2-negative ET cases 1, 2
2. Complete blood count with differential to assess for leukocytosis (suggests MPD) or anemia (suggests MDS or reactive cause) 1
3. Peripheral blood smear to evaluate platelet morphology and exclude left-shifted granulopoiesis 1, 3
4. Iron studies (ferritin, serum iron, TIBC, transferrin saturation) to exclude iron deficiency 4, 3
5. Inflammatory markers (CRP, ESR) to screen for inflammatory conditions 4, 3

If Initial Testing is Non-Diagnostic

• Bone marrow biopsy with reticulin staining is mandatory to distinguish ET from pre-PMF and to confirm clonal megakaryocyte proliferation versus reactive changes 1
• Cytogenetic analysis to detect clonal markers (abnormal karyotype in <10% of ET: +9, 20q-, 13q-) 2
• Comprehensive metabolic panel and imaging (chest X-ray, abdominal ultrasound) to exclude occult malignancy or infection 4, 3

Critical Clinical Pitfalls

Do Not Assume Reactive Thrombocytosis Without Workup

• A platelet count of 661 × 10⁹/L falls in the range where both primary and secondary causes overlap 3, 5
• Failure to test for CALR/MPL mutations will miss 25-35% of ET cases that are JAK2-negative 1, 2
• Reactive thrombocytosis does not require antiplatelet therapy or cytoreduction, while ET may require both depending on risk stratification 6, 4

Distinguish ET from Pre-Fibrotic PMF

• Pre-PMF has significantly worse prognosis (median survival 8-14 years vs. >35 years for ET in young patients) 2
• Bone marrow morphology is the key differentiator: pre-PMF shows extensive dense megakaryocyte clustering with marked atypia and cloud-like nuclei, while ET shows loose clusters of mature-appearing megakaryocytes 1

Thrombotic Risk Assessment Depends on Etiology

• Primary thrombocytosis (ET) carries significantly higher thrombotic risk than reactive thrombocytosis, even at similar platelet counts 6, 3
• If ET is confirmed, risk stratification determines treatment: high-risk (age >60 or prior thrombosis) requires cytoreduction with hydroxyurea; low-risk may only need aspirin or observation 6, 7, 2
• CALR-mutated ET has lower thrombotic risk than JAK2-mutated ET, which influences aspirin recommendations 1, 2

Extreme Thrombocytosis Considerations

• If platelet count exceeds 1,500 × 10⁹/L, withhold aspirin due to acquired von Willebrand syndrome causing paradoxical bleeding risk 6, 2
• Your patient at 661 × 10⁹/L does not meet this threshold 6